An increasing variety of diseases are being shown to be due to immunological processes, including diabetes, and now Alzheimer's disease (AD). AD is the most prevalent age-associated disease and growing evidence suggests that aspects of the innate immune system play a major role its progression. Based on this evidence, we propose a new approach to the treatment of AD by targeting key properties of the innate immune system involved in the progression of the disease. Microglia (or brain macrophages) are the resident immune cells of the brain. Not only are they implicated in the pathogenesis of a variety of neurological disorders including AD but they also play important, protective roles in the CNS. Thus, modulating the response of microglia following activation to favor their neuroprotective over their neurotoxic properties may be the key to harnessing the immune system to treat AD. Our studies have led to the identification of a molecule that controls microglial properties in ways that are beneficial for modulating AD progression. This is the flavonoid fisetin which our in vitro and animal studies have demonstrated inhibits TNF production in activated macrophages and microglia. Fisetin promotes the adoption of the M2 anti-inflammatory phenotype by microglia as manifested by an increase in the expression of CD45, a cell surface protein tyrosine phosphatase expressed exclusively by cells of hematopoietic lineages and by inhibition of iNOS induction. CD45 has been implicated in the inhibition of classical M1 microglial activation while driving the anti-inflammatory M2 microglial phenotype. Fisetin, a rare natural flavonoid, was initially identified in the Maher laboratory as a orally active, novel neuroprotective and cognition-enhancing molecule. Fisetin protects nerve cells from multiple toxic insults and is therapeutically active in rigorous rodent models for memory, rabbit and mouse models for ischemic stroke, mouse and fly models of Huntington's disease and in transgenic AD mice. A series of much more potent fisetin derivatives, many of which maintain in vitro anti-inflammatory activity, has recently been synthesized by SAR-driven iterative chemistry. From the 150 derivatives synthesized, we selected the best seven derivatives that maintain the biological activities of fisetin, including its anti-inflammatory actvity. Preliminary assays to assess their pharmacological properties indicate that these derivatives have the potential to be good CNS drugs. In addition, the derivatives do not suffer from the intellectual property challenges of the natural product fisetin and are covered under several issued and/or pending patents held by the Salk Institute. We propose to advance fisetin derivatives as modulators of innate immune function and clinical candidates for the treatment of AD. Specifically, we plan to (1) further characterize the induction of the M2 microglial phenotype by fisetin and fisetin derivatives in vitro; (2) identify which of the pre-selected fisetin derivatves induce the M2 phenotype in vivo and then determine which have pharmacokinetic properties most consistent with good CNS drugs and (3) test the best two fisetin derivatives in AD transgenic mice for effects on behavior and pathology.